CDE对制剂工艺中过量灌装与过量投料的审评尺度
摘要：制剂生产工艺中过量灌装（overfill）与过量投料（overage）不同，CDE对这两种过量方式的审评尺度也存在较大差异，本文从相关概念、各国法规政策的相关要求入手，对其二者进行区分，以便更好的明确制剂工艺的投药量，不足和缺陷之处望批评指正。
一、定义：
过量投料（过量加入），如已知某一成分在生产或贮存期间含量会降低，生产时可适当增加投料量，以保证在有效期内含量能符合规定。"An overageis a fixed amount of the drug substance in the dosage form that is added inexcess of the label claim." FDA Guidance Drug Product Chemistry,Manufacturing, and Controls Information 2003 Draft EMA DevelopmentPharmaceutics.
过量灌装（过量装量），是指使用时因包材的粘附而损失需要过量灌装的情况，特别是注射剂，需要考虑西林瓶/安瓿瓶，甚至针筒的粘附损失，目的是确保给药剂量。Overfill is the volume or weight of the formulation filled in eachcontainer in sliaht excess of the labeled content. Allowable excess volume mayalso be referred to as overfill. FDA Guidance Allowable Excess Volume andLabeled Vial Fill Size in Injectable Drug and Biological Products、FDA Guidance Drug ProductChemistry, Manufacturing, and Controls Information 2003 Draft.
二、制剂工艺中的过量投料
过量投料中包括化学损耗和物料损耗，详述如下：
化学损耗: 在样品制备及储存过程中引起药物的降解，造成药物有效含量下降。ICHQ8(R2)中指出，一般不提倡在药品生产中过量使用原料药，以补偿药品在生产或其有效期内的降解。但是有些药物稳定性极差，目前的生产工艺水平不能完全抑制其降解且降解产物不会造成安全性风险，故仍允许过量。如维生素A的制剂可允许过量20％。
物理损耗：在药物制剂工艺中，固体制剂存在制粒、混合、整粒，压片、分包装等多个环节存在着原辅料损失的可能；在液体制剂的工艺中，存在着管道及镀层的金属对药物的吸附等损耗；外用半固体软膏剂的制备中，常需要适当加温以促进脂质原料的溶解，在半成品的不同容器间的转移，和分装工序中也都存在一定的死体积，造成物料的损失；特殊剂型如缓控释功能的激光打孔渗透泵片剂，外层是坚硬的半透膜，内部是双层，一层为含药层，另一层为吸水后具有高渗的驱动层，由于此类制剂本身的固有缺陷以及API本身的理化性质特点，总要有极少部分在片剂有效的运转途径的最终点不能完全被泵出或者药物存在反渗透现象而使少部分药物储留于片壳内，为了使药品的有效性得以保持，所以需要过量投料。例如辉瑞公司生产的格列吡嗪缓释片过量10%；甲磺酸多沙唑嗪控释片过量5%；硝苯地平控释片过量10%。大多数物理性损耗中，原辅料是等比例的，风险较小。总之，目前审评中可接受过量投料的唯一理由是参比中有相同的过量，并在生产处方中列明各组分过量的依据。
ICH Q8 PharmaceuticalDevelopment
In general,use of an overage of a drug substance to compensate fordegradation during manufacture or a product's shelf life, or to extend shelflife，isdiscouraged.Any overages in the manufacture of the drug product，whether they appear in the finalformulated product or not，should be justified considering the safety and efficacy of theproduct. Information should be provided on the 1) amount of overage，2) reason for the overage (e.g.，to compensate for expected anddocumented manufacturing losses),and 3) justification for the amount of overageThe overage should be included in the amount of drug substance listed in thebatch formula (3.2.P.3.2)."
不鼓励过量加入来补偿生产或者货架期内的产品降解，对于过量加入，应提供依据并列明在生产处方中。
EMA Development Pharmaceutics
Overages are primarily employed to cover losses during manufactureof active substances or key excipients,i.e. manufacturing overage, and/orduring shelf-life i.e. stability overage. These can be distinguished since inthe former case there is unlikely to be increased dosage administered to thepatient， whereas thestability overage will result in overdosing where batches of product may reachthe patient soon after release.The inclusion of any overage should bejustified. Large overages (for example in excess of 10%) should not normally beused to cover up inherently unstable formulations it is better to reduce ashelf life rather than to risk exposing a patient to excessive doses of a drug.Similarly overages should not be used to cover up imprecise or inaccurateanalytical test procedures or sub-optimal manufacturing processes. Theintroduction of an overage of an active substance into a formulation shouldalways be justified on the grounds of safety and efficacy of the product. Itshould also be remembered that over dosage may be introduced by the mechanismof delivery, e.g. deposition of a metered-dose inhaled drug in the mouth.
应以临床安全，有效为出发点，区分是生产损失过量加入还是货架期损失过量加入。
三、小容量注射剂的过量灌装
液体药物通常必须通过中介设备（例如注射器）进行给药，通常很难从小瓶中取出100％的内容物。
2020版《中国药典》0102注射剂中规定，注射剂的灌装标示装量不大于50ml时，可参照下表适量增加装量。
2017年CDE发布的《已上市化学仿制药（注射剂）一致性评价技术要求》规定过量灌装量要和原研一致。
FDA药典相关规定，旨在“在没有适当理由的情况下，减少小瓶的过量灌装，以期减少用药错误、不良事件和液体药物产品的滥用”但并未提出一个严格的框架来对产品进行一刀切的监管。如果企业确实需要过量灌装，企业应遵守美国药典（USP）通用章节<1151>，该章节建议企业设计产品“以符合标签要求和可接受的过量灌装，并允许正确的剂量”。需要通过使用“可提取的内容测试数据”来证明偏差。此类数据应包括在产品申请批准中，并代表商业化过程。举例：某无菌粉灌装品种需达到100mg的剂量，灌装107.5mg无菌粉，临床使用时注入4.3ml配伍溶液，抽取4.0ml溶液，可确保临床使用量（即0.3ml的死体积），该品种的过量灌装为7.5%。
FDA的法规指南
Location Issues in Drug Product: 3.2.P,The use of an over-fillshould be indicated in 3.2.P.1. The rationale for an overfill should beincluded in 3.2.P.2.2.1.
FDA will RTR an ANDA whose subject is a parenteral drug product ifits fill volume deviates from the RLD drug product and the deviationis not permitted. ANDA parenteral drug products should contain the sameconcentration and total drug content per container as the RLD. Therefore, adeviation from the fill volume (total drug content) of the RLD parenteral drugproduct may constitute a change in strength. A change in strength mustfirst be approved via the suitability petition process before it can beproposed in an ANDA submission That is, alterations beyond overfill allowancesthat are within USP recommendations in a relevant drug product monograph.
注射剂装量应与RLD一致，如不一致(对于RLD的装量改变，超出了药典有关品种专论中建议的过量灌装范围)，应事先经适用性请愿程序批准，否则会RTR。
EMA关于过量灌装
1、250micrograms powder for solution for injection should be reconstituted with 0.72ml sterile water for injections, yielding a deliverable volume of 0.5 ml. An additionaloverfill is included in each vial to ensure that 250 µg of romiplostim can bedelivered. EMA Nplate.
2、For the 100mg vial, a 4.30 ml fill containing 107.5 mg bevacizumab (7,5% overfill)achieves delivery of 100 mg bevacizumab.EMA Avastin
小瓶包装死体积及复溶损失导致的过量。
四、如何区分参比是过量灌装还是过量投料
以某无菌粉灌装为例，规格为500mg，原研说明书规定主成分与辅料比例为1:0.725，参比反向工程中，测定主成分含量为105%，辅料的含量为103.6%，不同配伍溶剂，可提取的内容性损失最大约为4.5%，符合2020版《中国药典》0102注射剂中规定，因此该品种为过量灌装；对于过量投料，本人未经历过相关案例，根据ICHQ8相关要求，总体来说，不鼓励加入过量原料药以补偿生产过程或产品存贮期中原料药的降解，或用以延长保存期。
对于制剂生产过程中出现的过量现象，无论其是否是出现在最终制剂中，都应当要从产品的安全性和有效性方面对其进行合理性说明。应提供如下信息：1）过量的量；2）过量的原因（如，补偿生产过程中出现的损失）；3）超出量的合理性说明应分别在制剂处方组成2.3.P.1、3.2.P.1和制剂生产2.3.P.3、3.2.P.3部分讨论过量加入的原因。
五、参考文献
[1] 浅析药物制备工艺中的“过量投料”现象—中国药审.
[2]USP<1151>.
[3]Allowable-Excess-Volume-Labeled-Vial-Fill-Size-in-Injectable-Drug-and-Biological-Products
[4] ICH Q8 Pharmaceutical Development.
[ 5] FDA Guidance Allowable Excess Volume and Labeled Vial Fill Sizein Injectable Drug and Biological Products.
[6] EMA Avastin/ Nplate.